In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F17%3A10364360" target="_blank" >RIV/00216208:11160/17:10364360 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/71009396:_____/17:N0000003

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0223523417302039" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0223523417302039</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2017.03.047" target="_blank" >10.1016/j.ejmech.2017.03.047</a>

Jazyk výsledku

angličtina

Název v původním jazyce

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Popis výsledku v původním jazyce

Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H(37)Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond linked salicylanilide-amino acid fragment as the smallest active metabolite. (C) 2017 Published by Elsevier Masson SAS.

Název v anglickém jazyce

In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates

Popis výsledku anglicky

Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H(37)Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond linked salicylanilide-amino acid fragment as the smallest active metabolite. (C) 2017 Published by Elsevier Masson SAS.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GJ17-27514Y" target="_blank" >GJ17-27514Y: Peptidové drug delivery systémy směrované do makrofágů pro antimykobakteriálně aktivní sloučeniny</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Svazek periodika

133

Číslo periodika v rámci svazku

June

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

22

Strana od-do

152-173

Kód UT WoS článku

000401388900013

EID výsledku v databázi Scopus

2-s2.0-85016719558